Skin external preparation

ABSTRACT

The present invention provides a skin external preparation comprising a compound of the formula (1), (2), (3) or (4). ##STR1## wherein X represents COOH, etc., Z represents CONH 2 , etc. and R 1  and R 7  individually represent a hydrogen atom, etc. 
     The above-described compound has excellent effects, for example, for preventing or alleviating skin aging or inhibiting hair growth.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a skin external preparation havingeffects for preventing or alleviating skin aging or for inhibiting hairgrowth.

2. Description of the Related Art

As a result of researches on the aging of the skin, influences of aging,drying, oxidation, sun light (ultraviolet ray) and the like arementioned as the causes for the aging of the skin. The aging of the skinis recognized by a decrease of collagen or elastin in the dermis of theskin, a decrease in mucopolysaccharides including hyaluronic acid,cellular damage by ultraviolet rays or the like.

For the prevention of wrinkle formation, however, sufficient effectshave not yet been attained, for example, by a collagen-containingcosmetic composition. In addition, various researches have been made onthe aging of the skin caused by exposure to ultraviolet rays inconsideration of the relation with ultraviolet rays, however, a cosmeticcomposition superseding an ultraviolet absorber or ultraviolet protectorhas not yet been developed.

There is an increasing tendency to have a liking for a hairless body,particularly, hairless arms or legs, from the viewpoint of aestheticappearance. In order to remove the body hair, various methods have beenmade use of, for example, a mechanical removing method by using ashaver, a pair of hair-tweezers or the like, a method of removing thehair even from the hair bulb by using a depilatory agent and a method ofremoving the body hair by the chemical action of a depilatory agent.

The above-described hair removing methods however give physical orchemical stimulation to the skin and in addition, are limited inmaintaining the removed state. There is accordingly a demand for thedevelopment of a method which facilitates the body hair removal.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a skin externalpreparation having effects for preventing or alleviating the aging ofthe skin such as formation of wrinkles or for inhibiting hair growth.

The present invention relates to a skin external preparation comprisinga compound represented by any one of the following formulas (1), (2),(3) and (4): ##STR2## wherein X represents --COOR³, ##STR3## Zrepresents --CON(R⁸)R⁹ or --COOR¹⁰, R¹ represents a hydrogen atom or asubstituted or unsubstituted alkyl, alkenyl, aralkyl or alkoxy group, orwith R², may form a heterocyclic ring together with the adjacentnitrogen atom,

R² represents a hydrogen atom or a C₁₋₆ alkyl or alkenyl group, or withR¹, may form said heterocyclic ring,

R³, R⁸, R⁹ and R¹⁰ individually represent a hydrogen atom, an alkylgroup or an alkenyl group,

R⁴, R⁵ and R⁶ individually represents a hydrogen atom, an alkyl group,an alkenyl group or an aralkyl group, and

R⁷ represents an aralkyl group; ##STR4## wherein R¹¹ represents ahydrogen atom or a C₁₋₁₂ alkyl or alkenyl group,

R¹² and R¹⁴ individually represent a hydrogen atom or a C₁₋₈ alkylgroup,

R¹³ represents a hydrogen atom or a substituted or unsubstituted alkyl,alkenyl or aralkyl group, or with R¹⁵, may form a heterocyclic ringtogether with the adjacent nitrogen atom, and

R¹⁵ represents a hydrogen atom or with R¹³, may form said heterocyclicring; ##STR5## wherein R¹⁶ and R¹⁷ individually represent a hydrogenatom or an alkyl or alkenyl group, and

R¹⁸ and R¹⁹ individually represent a hydrogen atom, an aralkyl group ora substituted or unsubstituted alkyl or alkenyl group; ##STR6## whereinR²⁰ represents a hydrogen atom, a C₁₋₈ alkyl or alkenyl group or anaralkyl group,

R²¹ represents a hydrogen atom or a substituted or unsubstituted alkyl,alkenyl or aralkyl group,

R²² represents a hydrogen atom or a C₁₋₆ alkyl or alkenyl group, or withR²³, may form a heterocyclic ring with the adjacent nitrogen atom,

R²³ represents a hydrogen atom or a substituted or unsubstituted alkyl,alkenyl or aralkyl group, or with R²², may form said heterocyclic ring,

R²⁴ represents a hydrogen atom or a C₁₋₈ alkyl or alkenyl group, and

n stands for an integer of 0 to 5.

In the above formula (2), the compound represented by the followingformula (2a): ##STR7## wherein R^(12a) represents a hydrogen atom or aC₁₋₈ alkyl group, R^(13a) represents a hydrogen atom or an alkyl oraralkyl group which may be substituted by a carbamoyl group, R^(15a)represents a hydrogen atom or with R^(13a), may form a pyrrolidinyl orpiperidinyl group together with the adjacent nitrogen atom; or a saltthereof is novel and the present invention also provides this compoundor salt thereof.

The skin external preparation according to the present invention hasexcellent effects for preventing or alleviating the aging of the skin orfor inhibiting hair growth and can be synthesized easily.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A description will next be made of the compound of the formula (1).

In the formula (1), R¹ preferably represents a hydrogen atom, a C₁₋₁₂alkyl or alkenyl group which may have a substituent, a C₇₋₁₆ aralkylgroup or a C₁₋₁₂ alkoxy group. As the alkyl or alkenyl group which mayhave a substituent, a linear or branched C₁ -₁₂ alkyl or alkenyl group,and a C₁₆ alkyl or alkenyl group having a substituent such as carbamoyl,hydroxy or carboxyl group are more preferred, of which linear orbranched C₃₋₅ alkyl or alkenyl groups and C₁₋₄ alkyl or alkenyl groupshaving the above-described substituent are still more preferred. Amongthem, preferred examples include n-propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, carbamoylmethyl, 2-carbamoylethyl andhydroxymethyl groups. Examples of the aralkyl group include phenylalkyland naphthylalkyl groups, of which phenyl-C₁₋₆ alkyl groups arepreferred, with benzyl and phenetyl groups being more preferred. As thealkoxy group, linear or branched C₁₋₈ alkoxy groups are preferred.

X represents --COOR³, ##STR8## being preferred. As R³, a hydrogen atomand C₁₋₁₂ alkyl or alkenyl groups are preferred, with a hydrogen atom,and methyl, ethyl, n-propyl, n-butyl and isobutyl groups areparticularly preferred. As each of R⁴, R⁵ and R⁶, a hydrogen atom , C₁₋₆alkyl or alkenyl groups and C₇₋₁₆ alkyl groups are preferred, with ahydrogen atom and methyl, ethyl and benzyl groups being particularlypreferred. As R⁷, C₇₋₁₆ aralkyl groups are preferred, with benzyl andphenethyl groups being particularly preferred.

R² is preferred when it represents a hydrogen atom or a C₁₋₆ alkyl oralkenyl group, or it is coupled with R¹ to form a pyrrolidine ring. Zrepresents --CON(R⁸)R⁹ or --COOR¹⁰, with the --CON(R⁸)R⁹ beingpreferred. As each of R⁸, R⁹ and R¹⁰, a hydrogen atom and C₁₋₆ alkyl oralkenyl groups are preferred, with a hydrogen atom being more preferred.

A description will next be made of the compound of the formula (2).

In the formula (2), as R¹¹, a hydrogen atom and C₁₋₆ alkyl groups arepreferred, with a hydrogen atom and methyl, ethyl, n-propyl, isopropyl,n-butyl and isobutyl groups being particularly preferred. As each of R¹²and R¹⁴, a hydrogen atom and C₁₋₆ alkyl groups are preferred, with ahydrogen atom and methyl group being particularly preferred. As R¹⁴, thehydrogen atom is particularly preferred. As R¹³, a hydrogen atom, C₁₋₆alkyl or alkenyl groups each of which may be substituted with acarbamoyl group and C₇₋₁₆ aralkyl groups are preferred, with a hydrogenatom, C₁₋₄ alkyl or alkenyl groups each of which may be substituted witha carbamoyl group and phenyl-C₁₋₆ alkyl groups being more preferred andisopropyl, isobutyl, sec-butyl, benzyl and 2-(carbamoyl)ethyl groupsbeing particularly preferred. R¹⁵ is particularly preferred when itrepresents a hydrogen atom or with R¹³, forms a pyrrolidinyl orpiperidinyl group together with the adjacent nitrogen atom.

A description will next be made of the compound of the formula (3).

In the formula (3), as each of R¹⁶ and R¹⁷, a hydrogen atom and C₁₋₆alkyl or alkenyl groups are preferred, with a hydrogen atom and methyl,n-propyl, isopropyl, n-butyl and isobutyl groups being particularlypreferred. Preferred examples of each of R¹⁸ and R¹⁹ include a hydrogenatom, phenylalkyl groups (particularly, phenyl-C₁₋₆ alkyl groups),naphthylalkyl groups (particularly, naphthyl-C₁₋₆ alkyl groups) and C₁₋₅alkyl or alkenyl groups each of which may be substituted with ahydroxyl, methylthio, amino or 3-indolyl groups. Among them, thehydrogen atom and benzyl, isopropyl, isobutyl, sec-butyl,1-hydroxyethyl, 2-(methylthio)ethyl group, 4-aminobutyl group and3-indolylmethyl groups are particularly preferred.

A description will next be made of the compound of the formula (4).

In the formula (4), as R²⁰, a hydrogen atom, C₁₋₄ alkyl or alkenylgroups and aralkyl groups are preferred, with a hydrogen atom andmethyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl groups areparticularly preferred. Examples of the aralkyl group includephenylalkyl, biphenylalkyl and naphthylalkyl groups, of whichphenyl-C₁₋₆ alkyl and biphenyl-C₁₋₆ alkyl groups are preferred, withbenzyl and 4-phenylbenzyl groups being more preferred.

As R²², a hydrogen atom is most preferred.

As each of R²¹ and R²³, a hydrogen atom, linear or branched C₁₋₁₂ alkylor alkenyl groups and aralkyl groups are preferred, of which a hydrogenatom, linear or branched C₃₋₆ alkyl or alkenyl groups are morepreferred, with a hydrogen atom and n-propyl, isopropyl, isobutyl,sec-butyl and tert-butyl groups being particularly preferred. Examplesof the aralkyl group include phenylalkyl and naphthylalkyl groups, ofwhich phenyl-C₁₋₆ alkyl groups are preferred, with benzyl and phenethylgroups are still more preferred.

As R²⁴, a hydrogen atom and C₁₋₄ alkyl or alkenyl groups are preferred,with a hydrogen atom and methyl, ethyl, n-propyl, isopropyl, n-butyl andisobutyl groups being particularly preferred.

As n, 0 or 1 is most preferred.

Examples of the salt of each of the compounds (1), (2), (3) and (4)include alkali metal salts, alkaline earth metal salts, amine salts,amino acid salts and acid addition salts, of which alkali metal saltsand amino acid salts are preferred. The compound of each of the formulas(1) to (4) may have optical activity and its steric configuration may beany one of R, S and racemic forms. The compound may also be in the formof a hydrate.

Among the compounds of the formula (1), the following compounds areparticularly preferred. ##STR9##

Among the compounds of the formula (2), the following compounds areparticularly preferred. ##STR10##

Among the compounds of the formula (3), the following compounds areparticularly preferred. ##STR11##

Among the compounds of the formula (4), the following compounds areparticularly preferred. ##STR12##

Each of the compounds of the formula (1) can be prepared, for example,in accordance with the procedure described in Nobuo Izumiya et al.,"Peptide Gosei no Kiso to Jikken (Base and Experiment for PeptideSynthesis)", 18-19, Maruzen, Tokyo. Described specifically, the targetcompound can be prepared by reacting the hydrochloride of an amidecompound [H₂ N--CH(R¹)--CONH₂ ] with a halogenated formate ester,halogenated phosphate ester or the like in the presence of a base suchas amine and then, reacting the resulting product with a base such aspotassium hydroxide if necessary.

The compound of the formula (2) can be prepared, for example, by thefollowing process: ##STR13## wherein R¹¹ to R¹⁵ have the same meaningsas described above and X represents a halogen atom.

A glycinamide derivative (5) is reacted with a halogenocarboxylic acidderivative (6) in the presence of a base such as sodium hydroxide. Thereaction temperature of from -20 to 200° C. and the reaction time offrom 10 minutes to 24 hours are preferred. The reaction mixture is thenneutralized with an acid such as hydrochloric acid, followed byadditional treatments such as drying and isolation if necessary, wherebythe compound of the formula (2) can be obtained [see T. Miyazawa, Bull.Chem. Soc. Jpn., 53, 2555(1980)].

The compound of the formula (3) can be prepared, for example, byreacting a dipeptide with a halogenated formate ester in the presence ofa base such as amine (see the above-described "Basis and Experiment ofPeptide Synthesis").

The compound of the formula (4) can be synthesized, for example, by theprocess of Nakano et al. [Chem. Lett., 505-8(1990)] as shown by thefollowing reaction scheme: ##STR14## wherein R²⁰ to R²⁴ and n have thesame meanings as described above.

Described specifically, a half ester of malonic acid (7) and an aminoacid ester (8) are reacted in the presence of a dehydrating condensationagent. The reaction mixture is reacted with a base such as sodiumhydroxide as needed, whereby the target product is obtained. Thecompound of the formula (4) can also be synthesized by the process ofKatsuki et al. [Bull. Chem. Soc. Jpn., 49, 3287-3290(1976)] shown by thefollowing reaction scheme: ##STR15## wherein R²⁰ to R²⁵ and n have thesame meanings as described above.

Described specifically, a malonic acid half ester acid chloride (9) isreacted with an amino acid ester (8) in the presence of a base. Thereaction mixture is then alkylated by an alkyl halide or hydrolyzed by abase such as sodium hydroxide as needed, whereby the target product isobtained.

Although there is no particular limitation imposed on the amount of anyone of the compounds of the formulas (1) to (4) to be incorporated inthe skin external preparation of the present invention, an amount of0.0001 to 40 wt. % based on the whole composition is preferred, with0.01 to 20 wt. being particularly preferred.

It is particularly preferred to administer the skin external preparationof the present invention for the purpose of alleviating or preventingskin troubles caused by aging of the skin such as wrinkles, sagging andlowering in resilience, or of inhibiting hair growth.

The present inventors have carried out an investigation on the hairgrowth inhibitory action of various plant extracts as well as that ofthe above-described compounds. As a result, it has been found that aplant extract selected from hydrolyzed almond, burnet, clove, rose hips,hawthorn, betula and gambir has excellent hair growth inhibitory actionand among them, the hydrolyzed almond extract and clove extract havesuperior hair growth inhibitory action.

The term "hydrolyzed almond" as used herein means a mixture available bythe hydrolysis of seeds (sweet almond) of almond (Prunus amygdalusBatsch) belonging to Rosaceae in the presence of an acid or alkali. Theterm "burnet" means the root and rootstock of burnet (Sanguisorba officinalis L.) belonging to Rosaceae. The term "clove" means the bud ofclove (Syzygium aromaticum Merrill et Perry (Eugenia caryophyllataThunberg)) belonging to Myrtaceae. The term "rose hips" means the fruitof a wild rose (Rosa multiflora Thunberg) belonging to Rosaceae or aplant analogous thereto. The term "hawthorn" means the terrestrial partof the hawthorn (Craegus oxyacanth L.) belonging to Rosaceae. The term"betula" means the leaf, bark and wood parts of European betula (Betulaalba L.) belonging to Butulaceae. The term "gambir" means the driedsolid of a water extract from the leaves and young branches of Uncariagambir Roxburgh belonging to Rubiaceae. These plants have beenconventionally used as a herbal and crude drug or food.

The above-described plant extracts, other than the hydrolyzed almond, tobe used in the present invention, mean solvent extracts, or dilutedsolutions, concentrates or dried powders thereof each available bypulverizing the plant, extracting the resulting particles with a solventat room temperature or under heat or extracting by an extractor such asSoxhlet's extractor.

Examples of the extracting solvent include water, lower alcohols such asethanol, propanol and butanol, and polyols such as propylene glycol,1,3-butylene glycol and glycerin and mixtures thereof. Among them,single use of water or a mixture of ethanol or 1,3-butylene glycol andwater is preferred, with a 1:1 to 99:1 (volumetric ratio) mixture ofethanol or 1,3-butylene glycol and water being particularly preferred.

The hydrolyzed almond can be obtained, for example, by the followingprocess. Described specifically, it can be obtained by adding 0.1 to 20v/v % of an acid such as sulfuric acid, hydrochloric acid, acetic acidor phosphoric acid or a 0.01 to 10N alkali such as sodium hydroxide orpotassium hydroxide to one or a mixture of at least two of water,methanol, ethanol, propanol, butanol, propylene glycol and 1,3-butyleneglycol, preferably water and/or ethanol, immersing silk fibers in theresulting mixture generally at 3 to 100° C. and then removing insolublematters. This removal of the insoluble matters is preferably conductedafter adjusting the pH to about 7.0 with an alkali such as sodiumhydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonateor an acid such as sulfuric acid, hydrochloric acid, acetic acid orphosphoric acid in advance.

The above-described extracts can also be used after removal of inertmatters therefrom by a technique such as liquid-liquid distribution orremoval of a precipitate by adding a solvent. In the present invention,such an extract is preferably employed. The extract may also be usedafter treatment such as deodorization or decoloring in a known manner asneeded.

From the viewpoints of hair growth inhibitory effects, economy and thelike, the above-described plant extract is preferably added in an amountof 0.0001 to 50 wt. % as a dry solids content, with 0.001 to 10 wt. %,being particularly preferred.

Moreover, it is possible to incorporate a keratinization remedy in theskin external preparation of the present invention, thereby bringingabout an improvement in the effects for preventing or alleviating theaging of the skin which appears, for example, as wrinkle formation orfor inhibiting hair growth. Examples of the keratinization remedyinclude sphingosine derivatives.

In addition to the above-described effective ingredient andkeratinization remedy, any component can be incorporated in the skinexternal preparation of the present invention insofar as it does notimpair the advantages of the present invention. Examples includepurified water, alcohols, chelating agents, various oils, surfactants,emulsifiers, thickening agents, antiseptics, antioxidants, solvents,drug efficacy ingredients, powders, coloring matters and perfumes. It isalso possible to incorporate, in the skin external preparation of thepresent invention, an existing agent for preventing or alleviating skinaging, an existing hair growth inhibitor, an ultraviolet absorber, anultraviolet protector, collagen, a humectant, an anti-inflammatory, anantioxidant or the like as needed.

The skin external preparation of the present invention can be preparedin various forms in a conventional manner and preferred examples includelotion, emulsion, cream, ointment, stick, solution in an organicsolvent, purified water or the like, facial pack and gel. In otherwords, the skin external preparation of the present invention is used inthe form of a lotion, oil essence, O/W type or W/O type cream, emulsion,facial pack, ointment, foundation, skin cleansing agent, tonic orbathing agent.

EXAMPLES

The present invention will hereinafter be described in further detail byexamples. It should however be borne in mind that the present inventionis not limited to or by the examples.

Synthesis Example 1

Synthesis of N-iso-butoxycarbonyl-L-leucinamide (Compound 1-1)

In a mixed solvent of 150 ml of tetrahydrofuran and 50 ml of distilledwater, 5.00 g (30 mmol) of L-leucinamide hydrochloride and 5.46 g (54mmol) of triethylamine were dissolved, followed by ice cooling to 5° C.Without changing the temperature, 3.29 g (33 mmol) of isobutylchloroformate was added dropwise to the reaction mixture. After thecompletion of the dropwise addition, the full consumption of the rawmaterials was confirmed by thin layer chromatography. To the reactionmixture, 6.53 g (57 mmol) of 85% phosphoric acid was added to terminatethe reaction.

After tetrahydrofuran was distilled off from the reaction mixture underreduced pressure, 300 ml of ethyl acetate was added to the residue toextract the same. The organic layer was washed with distilled water andsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was then distilled off. The residue was subjected to columnchromatography with a mixed solvent of ethyl acetate and n-hexane as aneluent. The solvent was then distilled off, whereby 4.82 g (yield: 80%)of N-iso-butoxycarbonyl-L-leucinamide (Compound 1-1) was obtained. Theresulting compound has the following physical properties:

NMR(CDCl₃) δ: 0.85(d,3H,J=5 H), 0.88(d,3H,J=5 Hz), 1.33-1.93(m,4H),3.73(d,2H,J=7 Hz), 3.84-4.00(m,1H), 6.93(s,1H), 7.07(d,1H,J=9 Hz),7.26(s,1H).

Synthesis Example 2

Synthesis of N-carboxy-L-phenylalaninamide potassium salt(Compound 1-2)

In a mixed solvent of 150 ml of tetrahydrofuran and 50 ml of distilledwater, 6.00 g (30 mmol) of L-phenylalaninamide hydrochloride and 5.46 g(54 mmol) of triethylamine were dissolved, followed by ice cooling to 5°C. Without changing the temperature, 3.29 g (33 mmol) of isobutylchloroformate was added dropwise to the reaction mixture. After thecompletion of the dropwise addition, the full consumption of the rawmaterials was confirmed by thin layer chromatography. To the reactionmixture, 6.53 g (57 mmol) of 85a phosphoric acid was added to terminatethe reaction.

After tetrahydrofuran was distilled off from the reaction mixture underreduced pressure, 300 ml of ethyl acetate was added to the residue toextract the same. The organic layer was washed with distilled water andsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was then distilled off. The residue was dissolved in 100 ml ofethanol, followed by the addition of a solution of 1.35 g (24 mmol) ofpotassium hydroxide in 100 ml of distilled water while thoroughstirring. After stirring was continued at 70° C. for 3 hours, thereaction was terminated. The solvent was then distilled off and theresidue was recrystallized from ethanol-diethyl ether, whereby 5.91 g(yield: 81%) of N-carboxy-L-phenylalaninamide potassium salt (Compound1-2) was obtained as pale yellow crystals. The resulting compound hasthe following physical properties:

NMR(DMSO-d₆) δ: 2.58(dd,1H,J=8.14 Hz), 2.95(dd,1H,J=4.14 Hz),3.45(br.s,2H), 3.70-3.75(m,1H), 6.07(br.s,1H), 7.13-7.28(m,5H).

Synthesis Example 3

Synthesis of N-(dibenzyloxyphosphonyl)-L-leucinamide (Compound 1-3)

In 200 ml of chloroform, 6.0 g (36 mmol) of L-leucinamide hydrochlorideand 14.6 g (144 mmol) of triethylamine were dissolved, followed bycooling to 0° C. while through stirring. To the reaction mixture, 16.0 g(54 mmol) of dibenzyl chlorophosphate was added. Without changing thetemperature, stirring was continued for 20 hours. After the completionof the reaction, 50 ml of ethanol was added and the resulting mixturewas stirred for 30 minutes. The reaction mixture was washed successivelywith 5% hydrochloric acid, distilled water, a 10% aqueous solution ofsodium bicarbonate and saturated saline and then dried over anhydroussodium sulfate. The solvent was then distilled off under reducedpressure. The residue was subjected to column chromatography with amixed solvent of chloroform and ethanol as an eluent. After the solventwas distilled off, the residue was recrystallized from ethylacetate--n-hexane, whereby 9.3 g (yield: 66%) ofN-(dibenzyloxyphosphonyl)-L-leucinamide (Compound 1-3) was obtained aswhite crystals. The resulting compound has the following physicalproperties:

NMR(CDCl₃) δ: 0.84(d,3H,J=4 Hz), 0.87(d,3H,J=4 Hz), 1.41-1.82(m,3H),3.70-3.97(m,2H), 4.98(d,2H,J=4 Hz), 5.02(d,2H,J=4 Hz), 6.93(s,1H),7.07(d,1H,J=9 Hz), 7.26(s,1H).

Synthesis Example 4

Synthesis of N-phosphono-L-leucinamide dipotassium salt (Compound 1-4)

In 100 ml of methanol, 5.0 g (13 mmol) ofN-(dibenzyloxyphoshonyl)-L-leucinamide (Compound 1-3) was dissolved,followed by the addition of 3.3 ml of a 8N aqueous solution of potassiumhydroxide and 0.2 g of 10% palladium carbon. The resulting mixture wasstirred at room temperature for 2 hours under a hydrogen gas stream.After the completion of the reaction, the reaction mixture was filteredto remove the catalyst and the solvent was distilled off. The residuewas recrystallized from ethanol-diethyl ether, whereby 3.2 g (yield:97%) of N-phosphono-L-leucinamide dipotassium salt (Compound 1-4) wasobtained. The resulting compound has the following physical properties:

NMR(D₂ O) δ: 0.94(d,6H,J=6 Hz), 1.47-1.61(m,2H), 1.69-1.79(m,1H),3.43-3.76(m,1H).

Protons of any amide were not observed at all.

The compounds shown below were each obtained in a similar manner to oneof Synthesis Examples 1 to 4.

                                      TABLE 1                                     __________________________________________________________________________    Synthesis     Synthesizing                                                                        Yield                                                                            NMR                                                    Example                                                                            Compound process                                                                             %  Solvent                                                                            δ                                           __________________________________________________________________________    Synthesis                                                                          N-carboxy-L-                                                                           Synthesis                                                                           82%                                                                              DMSO-d.sub.6                                                                       0.87(d, 3H, J=6Hz), 0.88(d, 3H, J=6Hz),                                        Example 5 leucinamide Example 2   0.98-1.81(m                                , 3H), 3.50-3.72(m, 1H),                             potassium salt    5.86(br. s, 2H), 6.65(br. s, 1H)                            (Compound 1-5)                                                               Synthesis N-carboxy-D- Synthesis 78% DMSO-d.sub.6 0.86(d, 3H, J=6Hz),                                   0.88(d, 3H, J=6Hz),                                 Example 6 leucinamide Example 2   1.02-1.83(m, 3H), 3.70-3.74(m, 1H),                                     potassium salt    5.67(s, 1 H), 6.23(d, 1H,                                 J=7Hz), 6.52(s, 1H)                                  (Compound 1-6)                                                               Synthesis N-carboxy-L- Synthesis 73% DMSO-d.sub.6 1.10(d, 3H, J=7Hz),                                   3.37-3.42(m, 1H),                                   Example 7 alaninamide Example 2   6.10(br. s, 1H), 6.26(br. s, 1H),                                       potassium salt    6.41(br. s, 1H)                  (Compound 1-7)                                                               Synthesis N-carboxy-L- Synthesis 78% DMSO-d.sub.6 0.64(d, 3H, J=7Hz),                                   0.77-1.51(m, 6H), 1.57-                             Example 8 isoleucinamide Example 2   1.69(m, 1H), 3.41(d, 3H, J=3Hz),                                     potassium salt    3.50(d, 3H, J=3Hz),                                       6.20(s, 1H)                                          (Compound 1-8)                                                               Synthesis N-methoxycarbonyl- Synthesis 81% CDCl.sub.3 0.88(d, 6H,                                       J=7Hz), 0.90(d, 6H, J=6Hz),                         Example 9 L-leucinamide Example 1   1.37-1.92(m, 4H), 3.72(d, 2H,                                       J=6Hz), 3.87-                                        (Compound 1-9)    4.00(m, 1H), 6.92(s, 1H),                                       7.10(d, 1H, J=10Hz), 7.23(s, 1H)                                         Synthesis N-(diethoxy- Synthesis 62% CDCl.sub.3 0.94(d, 6H, J=6Hz),                                     1.30(t, 6H, J=7Hz),                                 Example phosphonyl)-L- Example 3   1.53-1.84(m, 3H), 3.61-3.75(m, 1H),                                  3.93-                                               10 leucinamide    4.11(m, 4H), 4.37(t, 1H, J=11 Hz),                           (Compound 1-10)    6.45(s, 2H), 7.34(s, 1H).                                 Synthesis N-carboxy-L- Synthesis 65% D.sub.2 O 3.88(s, 2H)                    Example glycinamide Example 2                                                 11 potassium salt                                                              (Compound 1-11)                                                              Synthesis N-(phenethyl- Synthesis 46% CDCl.sub.3 0.91(d, 6H, J=6Hz),                                    1.37-2.01(m, 5H), 2.76-                             Example phosphonyl)-L- Example 3, 4   2.89(m, 2H), 3.58-3.74(m, 1H),                                    7.13-                                               12 leucinamide    7.27(m, 7H)                                                  (Compound 1-12)    The hydroxyl group of the phosphonyl                           group was not observed at all.                                           Synthesis N-carboxy-L- Synthesis 33% D.sub.2 O 2.67-2.84(m, 2H),                                        4.40-4.55(m, 1H)                                    Example asparaginamide Example 2                                              13 potassium salt                                                              (Compound 1-13)                                                              Synthesis N-carboxyl-L- Synthesis 37% DMSO-d.sub.6 1 .51-1.90(m, 2H),                                   2.00-2.20(m, 1H), 2.70-                             Example prolinamide Example 2   2.98(m, 1H), 3.40-3.68(m, 2H), 8.31(s,                                  2H)                                                 14 potassium salt                                                              (Compound 1-14)                                                            __________________________________________________________________________

Synthesis Example 15

Synthesis of Compound 2-1

In a flask, 200 ml of water, 20 g of phenylalaninamide (0.12 mol), 9.7 g(0.24 mol) of sodium hydroxide and 14 g (0.12 mol) of sodiumchloroacetate were charged, followed by heating at 50° C. for 5 hours.After the completion of the reaction, about 7 g of hydrochloric acid wasadded to the reaction mixture to neutralize the same, followed by dryingunder reduced pressure, whereby 44 g of a mixture of Compound 2-1 andsodium chloride was obtained. By recrystallization (H₂ 0), Compound 2-1was isolated (yield: 67%).

NMR(DMSO-d₆) δ: 2.75-3.34(4H,m), 3.75(1H,t,J=6.7 Hz), 7.27(5H,m),7.57(1H,s), 7.76(1H,s).

Synthesis Examples 16 to 23

Compounds 2-2 to 2-9 shown in Tables 2 and 3 were synthesized in asimilar manner to Synthesis Example 15 by using the amide derivativesshown in Tables 2 and 3.

                                      TABLE 2                                     __________________________________________________________________________    Synthesis  Glycinamide                                                                          Halocarboxylic                                                                          NMR                                               Example                                                                            Compound                                                                            derivative                                                                           acid derivative                                                                      Yield                                                                            Solvent                                                                            δ                                      __________________________________________________________________________    16   Compound                                                                            Phenylalanin-                                                                        2-Chloro-                                                                            66%                                                                              DMSO-d.sub.6                                                                       1.22(3H, d, J=6.9Hz),                           2-2 amide propionic acid   2.25(1H, d, J=3.7Hz), 3.50-                             4.45(4H, m), 7.02-7.41(7H, m)                                           17 Compound Leucinamide Sodium 67% DMSO-d.sub.6 0.82-1.02(6H, m),                                              2-3  chloroacetate   1.54(2H, t,                                            J=6.6Hz), 1.46-                                      1.80(1H, m), 3.04-3.60(3H, m),                                                3.56(1H, t, J=7.1Hz), 7.50(1H, s),                                            7.86(1H, s)                                                             18 Compound Glutamic Chloroacetic 48% DMSO-d.sub.6 1.61-2.00(2H, s),                                         2.00-                                           2-4 acid diamide acid   2.38(4H, m), 2.99-3.30(1H, m),                             6.81(1H, d, J=15.6Hz),                                                        7.29(1H, d, J=30.0Hz),                                                        7.41(1H, d, J=15.6Hz),                                                        7.69(1H, d, J=31.4Hz)                                                   19 Compound Glutamic 2-Chloro- 68% DMSO-d.sub.6 1.16(3H, d, J=6.8Hz),                                        1.25-                                           2-5 acid diamide propionic acid   1.41(2H, m), 1.64-2.00(2H, m),                                                   2.00-2.36(2H, m), 7.0-                        7.86(4H, m)                                                           __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Synthesis  Glycinamide                                                                          Halocarboxylic                                                                          NMR                                               Example                                                                            Compound                                                                            derivative                                                                           acid derivative                                                                      Yield                                                                            Solvent                                                                            δ                                      __________________________________________________________________________    20   Compound                                                                            Asparatic                                                                            Chloroacetic                                                                         41%                                                                              DMSO-d.sub.6                                                                       2.92(2H, d, J=5.12Hz), 3.20-                    2-6 acid diamide acid   4.22(2H, m), 4.27(1H, m), 7.05-                            7.35(4H, m)                                                             21 Compound Asparatic 1-Chloro- 40% DMSO-d.sub.6 1.21(3H, d, J=6.92Hz),                                      3.23-                                           2-7 acid diamide propionic acid   4.71(4H, m), 6.98-7.17(2H, m),                                                   7.59-7.79(2H, m)                        22 Compound Prolinamide Chloroacetic 52% DMSO-d.sub.6 1.50-1.88(4H, m),                                      7.11(1H, s),                                    2-8  acid   1.90-2.22(1H, m), 7.38(1H, s),                                         2.40-2.60(1H, m), 2.97-                                                       3.33(1H, m), 3.27(2H, dd, J=44.9,                                             17.1Hz)                                                                 23 Compound Prolinamide 1-Chloro- 26% DMSO-d.sub.6 1.01-1.32(7H, m),                                         7.14(1H, s),                                    2-9  propionic acid   1.50-1.86(2H, m), 7.31(1H, s),                               2.61-2.83(1H, m),                                                             4.01(1H, g, J=6.9Hz)                                                  __________________________________________________________________________

Synthesis Example 24

Synthesis of Compound 3-1

In 50 ml of chloroform, 1.00 g (3.9 mmol) of L-leucyl-L-lucine methylester and 0.78 g (7.8 mmol) of triethylamine were dissolved, followed byice cooling to 5° C. Without changing the temperature, 0.59 g (4.3 mmol)of isobutyl chloroformate was added dropwise. After the completion ofthe dropwise addition, the full consumption of the raw materials wasconfirmed by thin-layer chromatography. To the reaction mixture, 0.49 g(4.3 mmol) of 85% phosphoric acid was added to terminate the reaction.The organic layer was washed with distilled water and saturated salineand then dried over anhydrous sodium sulfate. The solvent was distilledoff and the residue was subjected to column chromatography with an ethylacetate-n-hexane mixed solvent as an eluent. The solvent was thendistilled off, whereby 0.91 g (yield: 65%) of Compound 3-1 was obtained.

NMR(DMSO-d₆) δ: 0.83-0.90(m,18H), 1.01-1.93(m,7H), 3.61(s,3H),3.73(d,2H,J=7 Hz), 4.00-4.12(m,1H), 4.24-4.30(m,1H), 7.09(d,1H,J=8 Hz),8.12(d,1H,J=8 Hz).

Synthesis Example 25

Synthesis of Compound 3-2

In a mixed solvent of 20 ml of tetrahydrofuran and 10 ml of distilledwater, 1.00 g (4.1 mmol) of L-isoleucyl-L-isoleucine and 0.83 g (8.2mmol) of triethylamine were dissolved, followed by ice cooling to 5° C.Without changing the temperature, 0.43 g (4.5 mmol) of methylchloroformate was added dropwise. After the completion of the dropwiseaddition, the full consumption of the raw materials was confirmed bythin-layer chromatography. To the reaction mixture, 0.98 g (8.2 mmol) of85% phosphoric acid was added to terminate the reaction.

Tetrahydrofuran was distilled off from the reaction mixture underreduced pressure. To the residue, 100 ml of ethyl acetate was added toextract the same. The organic layer was washed with distilled water andsaturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off and the residue was dissolved in 20 ml ofethanol. While thorough stirring, a solution of 0.46 g (8.2 mmol) ofpotassium hydroxide in 20 ml of distilled water was added to theresulting solution, followed by stirring at 70° C. for 3 hours. Afterthe full consumption of the raw materials was confirmed by thin layerchromatography, 0.80 g (82 mmol) of 85% phosphoric acid was added toterminate the reaction. To the reaction mixture, 300 ml of ethyl acetatewas added to extract the same. The organic layer was washed withdistilled water and saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off and the residue wasrecrystallized from ethyl acetate-n-hexane, whereby 0.60 g (yield: 51%)of Compound 3-2 was obtained as white crystals.

NMR(DMSO-d₆) δ: 0.77-0.90(m,12H), 1.02-1.46(m,4H), 1.66-1.86(m,2H),4.01-4.14(m,1H), 4.20-4.27(m,1H), 6.31(d,1H,J=9 Hz), 6.41(d,1H,J=9 Hz),12.47(br.s,2H).

Synthesis Examples 26 to 28

Compounds 3-3 to 3-5 were synthesized in a similar manner to SynthesisExample 25 by using the dipeptide and chloroformate ester shown in Table4.

                                      TABLE 4                                     __________________________________________________________________________    Synthesis         Chloroformate                                                                           NMR                                               Example                                                                            Compound                                                                            Dipeptide                                                                            ester  Yield                                                                            Solvent                                                                            δ                                      __________________________________________________________________________    26   Compound                                                                            L-phenyl-                                                                            Methyl 55%                                                                              DMSO-d.sub.6                                                                       2.62-3.12(m, 4H), 3.45(s, 3H),                  3-3 alanyl-L- chloroformate   3.60(s, 3H), 4.20-4.31(m, 1H),                   phenylalanine    4.47-4.58(m, 1H), 7.17-                                      methyl ester    7.30(m, 11H), 8.43(d, 1H, J=8Hz)                            27 Compound L-leucyl- Methyl 61% DMSO-d.sub.6 0.87(d, 6H, J=7Hz), 1.40-        3-4 glycine chloroformate   1.47(m, 2H), 1.51-1.72(m, 1H),                     methyl ester    3.33(s, 3H), 3.61(s, 3H), 3.83-                                   3.63(m, 2H), 3.89-4.10(m, 1H),                                                7.11(d, 1H, J=8Hz),                                                           8.22(t, 1H, J=6Hz)                                                      28 Compound L-phenyl- Methyl 49% DMSO-d.sub.6 2.79-3.04(m, 2H),                                                3-5 alanyl-glycine chloroformate                                            3.67(d, 2H, J=6Hz), 4.28-                            4.38(m, 1H), 6.33-6.40(m, 2H),                                                7.15-7.30(m, 5H), 12.48(bs, 1H)                                       __________________________________________________________________________

Synthesis Example 29

Synthesis of Compound 4-1

In 50 ml of chloroform, 16.05 g (114 mmol) of glycine ethyl esterhydrochloride and 23.27 g (228 mmol) of triethylamine were dissolved,followed by ice cooling to 5° C. Without changing the temperature, 10.00g (57 mmol) of ethylmalonyl chloride was added dropwise to the resultingsolution. After the completion of the dropwise addition, the fullconsumption of the raw materials was confirmed by thin layerchromatography. To the reaction mixture, a 5% aqueous phosphoric acidsolution was added to terminate the reaction. The, organic layer waswashed with distilled water and saturated saline and then dried overanhydrous sodium sulfate. The solvent was distilled off. The residue wassubjected to column chromatography with a mixed solvent of ethyl acetateand n-hexane as an eluent. The solvent was distilled off, whereby 9.40 g(yield: 76%) of Compound 4-1 was obtained.

NMR(DMSO-d₆) δ: 2.48-2.51(m,6H), 3.30(d,2H,J=9 Hz), 3.85(d,2H,J=6 Hz),4.02-4.20(m,4H), 8.49(t,1H,J=5 Hz).

Synthesis Example 30

Synthesis of Compound 4-2

In 50 ml of dehydrated tetrahydrofuran, 5.00 g (23.0 mmol) of Compound4-1 was dissolved. The resulting solution was added to a suspension of1.10 g (27.6 mmol) of sodium hydride in 30 ml of tetrahydrofuran,followed by heating to 50° C. After the slow dropwise addition of 3.74 g(21.9 mmol) of benzyl bromide and stirring for three hours at the sametemperature, the reaction was terminated. After cooling, a 54 aqueoussolution of phosphoric acid was added to the reaction mixture, followedby extraction with 300 ml of ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium bicarbonate and saturatedsaline and-then dried over anhydrous sodium sulfate. The solvent wasdistilled off and the residue was subjected to chromatography with amixed solvent of ethyl acetate and n-hexane as an eluent. By distillingoff the solvent, 3.89 g (yield: 55%)) of Compound 4-2 was obtained.

NMR(DMSO-d₆) δ: 1.16(t,1H,J=7 Hz), 2.93-3.19(m,2H), 3.71(t,1H,J=7 Hz),3.80(d,2H,J=6 Hz), 4.06(q,4H,J=7 Hz), 7.13-7.29(m,5H), 8.61(t,1H,J=6Hz).

Synthesis Example 31

Synthesis of Compound 4-3

In 30 ml of methanol, 3.00 g (9.8 mmol) of Compound 4-2 was dissolved.To the resulting solution, a solution of 1.20 g (21.5 mmol) of potassiumhydride in 10 ml of water was added. After the resulting mixture wasstirred at room temperature for 2 hours, the reaction was terminated.Methanol was distilled off under reduced pressure. To the residue, a 5%aqueous solution of phosphoric acid was added and the resulting crystalswere collected by filtration. The crystals were washed with water andthen dried under reduced pressure, whereby 2.17 g (yield: 88%) ofCompound 4-3 was obtained.

NMR(DMSO-d₆) δ: 2.90(m,2H), 3.59(t,1H,J=7Hz), 3.74(d,2H,J=6 Hz),7.12-7.32(m,5H), 8.37(t,1H,J=6 Hz), 12.49(br.s,2H).

Synthesis Examples 32 to 34

Compounds 4-4 to 4-6 were synthesized in similar manners to SynthesisExamples 29 to 31 by using the amino acid ester and alkyl halide shownin Table 5.

                                      TABLE 5                                     __________________________________________________________________________    Synthesis                                                                          Synthesizing                                                               Example process Amino acid ester Alkyl halide Yield NMR                     __________________________________________________________________________    32   30    --      Bromo-                                                                              61%                                                                              DMSO-d.sub.6                                                                       1.14-1.25(m, 6H), 2.99-                           biphenyl-   3.20(m, 2H),                                                      methane   3.77(t, 1H, J=8Hz),                                                    3.87(d, 2H, J=8Hz), 3.98-                                                     4.19(m, 4H), 7.24-                                                            7.65(m, 9H),                                                                  8.63(t, 1H, J=5Hz)                                                      33 29 β-alanine methyl Benzyl- 55% DMSO-d.sub.6 2.15-2.39(m, 2H),                                       2.90-                                           30 ester hydro- bromide   3.09(m, 2H), 3.10-                                  31 chloride    3.34(m, 2H),                                                        3.54(t, 1H, J=8Hz), 7.00-                                                     7.35(m, 5H),                                                                  8.11(t, 1H, J=5Hz),                                                           12.38(br. s, 2H)                                                        34 29 L-phenylalanine -- 68% DMSO-d.sub.6 2.84-3.10(m, 2H), 3.17                                               31 methyl ester    (s, 2H), 4.42-4.53(m                                     , 1H),                                           hydrochloride    7.09-7.35(m, 5H),                                                8.35(d, 1H, J=8Hz),                                                           12.24(br. s, 2H)                                                      __________________________________________________________________________

Test 1: Wrinkle Formation Inhibition in a Hairless Rat

The back side of a hairless mouse (HR/ICR, 6 week age at the start ofthe test) was exposed to UV-B light by a health light lamp ("SE20",trade name; product of Toshiba Electric) at a dose adjusted to 1 MED orless/once. Immediately after the exposure, 100 μl of an 80% ethanolsolution (test substance) containing the test compound was applied. Theabove procedure was carried out for 20 weeks. The energy amount wasmeasured by a UV radiometer ("UVR-305/365D; manufactured by TokyoOptical Co.). For a control group, only 80% ethanol was applied andtested in the same way. After the test, the degree of wrinkles wereevaluated visually by the following criterion (wrinkle index). Theresults are shown in Table 6.

<Wrinkle Degree>

0: No wrinkle was formed.

1: A few shallow wrinkles were formed.

2: A slight amount of wrinkles was formed.

3: Some wrinkles were formed.

4: Deep wrinkles were formed.

                  TABLE 6                                                         ______________________________________                                                       Concentration                                                    Test substance of application Wrinkle index                                 ______________________________________                                        Control        --           3.06 ± 0.13                                      Compound 1-1 10 mM 2.05 ± 0.09                                             Compound 1-2 1 mM 1.93 ± 0.12                                              Compound 1-3 10 mM 2.91 ± 0.06                                             Compound 1-4 1 mM 1.62 ± 0.10                                              Compound 1-5 1 mM 1.69 ± 0.15                                              Compound 1-6 10 mM 2.63 ± 0.05                                             Compound 1-7 10 mM 2.88 ± 0.11                                             Compound 1-8 1 mM 1.81 ± 0.06                                              Compound 1-9 1 mM 2.21 ± 0.15                                              Compound 1-10 10 mM 2.68 ± 0.09                                            Compound 1-11 20 mM 2.83 ± 0.10                                            Compound 1-12 1 mM 1.68 ± 0.14                                             Compound 1-13 1 mM 1.87 ± 0.12                                             Compound 1-14 1 mM 1.71 ± 0.08                                             Compound 2-1 1 mM 1.13 ± 0.11                                              Compound 2-2 1 mM 1.62 ± 0.10                                              Compound 2-3 1 mM 2.08 ± 0.10                                              Compound 2-4 10 mM 2.88 ± 0.14                                             Compound 2-5 10 mM 1.98 ± 0.17                                             Compound 2-6 10 mM 2.48 ± 0.21                                             Compound 2-7 10 mM 2.56 ± 0.15                                             Compound 2-8 10 mM 1.69 ± 0.15                                             Compound 2-9 10 mM 1.93 ± 0.12                                             Compound 3-1 10 mM 1.69 ± 0.15                                             Compound 3-2 1 mM 1.93 ± 0.12                                              Compound 3-3 10 mM 2.88 ± 0.11                                             Compound 3-4 1 mM 1.62 ± 0.10                                              Compound 3-5 10 mM 2.43 ± 0.16                                             Compound 4-1 10 mM 2.42 ± 0.15                                             Compound 4-2 1 mM 1.25 ± 0.12                                              Compound 4-3 0.1 mM 2.01 ± 0.21                                            Compound 4-4 0.1 mM 1.81 ± 0.14                                            Compound 4-5 0.1 mM 1.44 ± 2.91                                            Compound 4-6 1 mM 1.83 ± 0.09                                            ______________________________________                                    

From the results of Table 6, it has been found that Compounds of theformulas (1) to (4) had marked wrinkle formation inhibitory action andshowed excellent effects for preventing or alleviating aging of theskin.

Test 2: Maintenance of Skin Elasticity in a Rat

The bottoms of the both hind feet of three-week old SD male rats wereclassified into 4 groups, that is, a test-substance (as a 80%) ethanolsolution) applied group, a solvent (80%) ethanol) applied group and anuntreated group. After exposure to UV-B light (1 MED or less), the testsubstance or solvent was applied in an amount of 10 μl/foot. The aboveprocedure was carried out on alternate days, three times a week for sixweeks.

The elasticity of the skin was determined by measuring the displacementfor 3 seconds after sucking of the skin was started at 500 mb and 3seconds after sucking was stopped, totally for 6 seconds, by using acutometer "SES575" (trade name, product of Courage Kazaka). Themeasurement was carried out five times/foot, whereby Ue and Uf valueswere found.

The linearity of elastic fibers was analyzed in accordance with themethod of Imokawa et al. [J. Invest. Dermatol., 105, 254-258(1995)]using image analysis of a SEM micrograph. Described specifically,samples for scanning electron microscope (SEM) were prepared by fixingthe bottom of a leg of a rat under reflux with Mercox (Dainippon Ink &Chemicals, Inc.), followed by digestion with formic acid. From SEMmicrographs (×1000) of each of the samples, typical ten micrographs wereselected and their enlarged copies were formed. The enlarged micrographswere each divided into 16 regions uniformly. From each of the regions,any one of the elastic fibers was selected and traced on a clear filmwith a line of a fixed width (8 pixel width). Provided that an areasurrounded by the line tracing the elastic fiber is A and thelongitudinal length and lateral length of the minimum rectanglesurrounding the trace are B and C, respectively, the linearity of theelastic fiber is represented by A/(B×C). For example, if the trace ofthe elastic fiber is linear, the linearity becomes 1. The results areshown in Table 7.

                                      TABLE 7                                     __________________________________________________________________________              Evaluated                                                             Tested substance concentration Ue value Uf value Linearity                  __________________________________________________________________________    Untreated group                                                                         --     0.03294 ± 0.01531*                                                                   0.04833 ± 0.01700*                                                                   0.7345 ± 0.0333*                        Solvent applied group -- 0.02125 ± 0.00875.sup.## 0.03333 ±                                                0.01111.sup.## 0.5133 ± 0.0600.sup                                         .##                                        Compound 1-5 0.2 wt. % 0.03269 ± 0.01313* 0.04800 ± 0.01833*                                               0.7330 ± 0.0367*                        Compound 1-12 0.3 wt. % 0.02969 ± 0.01344* 0.04311 ± 0.01678*.sup.                                         # 0.7067 ± 0.0653*                      Compound 2-1 0.2 wt. % 0.03269 ± 0.01313* 0.04800 ± 0.01833*                                               0.7330 ± 0.0367*                        Compound 2-2 0.3 wt. % 0.02969 ± 0.01344* 0.04311 ± 0.01678*.sup.#                                          0.7067 ± 0.0653*                       Compound 3-2 0.2 wt. % 0.03269 ± 0.01313* 0.04800 ± 0.01833*                                               0.7330 ± 0.0367*                        Compound 3-4 0.3 wt. % 0.02969 ± 0.01344* 0.04311 ± 0.01678*.sup.#                                          0.7067 ± 0.0653*                       Compound 4-2 0.1 wt. % 0.02341 ± 0.01344* 0.04711 ± 0.02133*                                               0.7221 ± 0.0299*                        Compound 4-3 0.1 wt. % 0.03359 ± 0.01131* 0.04323 ± 0.01722*                                               0.7013 ± 0.0655*                      __________________________________________________________________________     *: p < 0.005 (vs the solvent applied group)                                   .sup.# : p < 0.005 (vs the untreated group)                                   .sup.## : p < 0.005 (vs the untreated group)                             

From the results of Table 7, it has been found that the compounds of theformulas (1) to (4) showed effects for strongly preventing the loweringof the skin elasticity caused by UV-B and the deterioration of thethree-dimensional structure of the elastic fibers which will be a causefor the lowering, thereby maintaining the flexibility of the skin.

Test 3: Hair Growth Inhibition in a Mouse

The 2×4 cm² portion of the back of each of 6-week old C₃ H mice employedin groups, each consisting of five mice, was shaved by an electricclippers and electric shaver with a care so as not to injure the skin.To the shaved portion, a sample was applied in an amount of 100 μl twicea day for 4 weeks. The test substance was dissolved in a solvent (80%ethanol) to adjust its concentration as shown in Table 7. To the controlgroup, only the solvent was applied. After three weeks, in order toobserve the hair regrowth, the shaved portion was photographed at acertain magnification and by using an image analyzer, the area ratio ofthe regrown hair (area of regrown hair/shaved area) was compared withthat of the control group. The hair growth inhibition ratio wasindicated as a relative value (%) provided that the area ratio of theregrown hair of the control group was 100. The results are shown inTables 8 and 9.

                  TABLE 8                                                         ______________________________________                                                                  Hair growth                                             inhibition 3                                                                 Concentration weeks after                                                    Tested substance of application shaving                                     ______________________________________                                        Compound 1-1   1 mM       65.3%                                                 Compound 1-2 1 mM 52.6%                                                       Compound 1-3 10 mM 72.2%                                                      Compound 1-4 1 mM 60.3%                                                       Compound 1-5 1 mM 54.6%                                                       Compound 1-6 10 mM 53.8%                                                      Compound 1-7 10 mM 52.1%                                                      Compound 1-8 1 mM 60.5%                                                       Compound 1-9 1 mM 64.9%                                                       Compound 1-10 1 mM 73.1%                                                      Compound 1-11 20 mM 51.0%                                                     Compound 1-12 1 mM 71.3%                                                      Compound 1-13 1 mM 69.5%                                                      Compound 1-14 1 mM 70.6%                                                      Compound 2-1 1 mM 72.2%                                                       Compound 2-2 1 mM 60.3%                                                       Compound 2-3 1 mM 70.4%                                                       Compound 2-4 10 mM 42.3%                                                      Compound 2-5 10 mM 32.8%                                                      Compound 2-6 10 mM 48.9%                                                      Compound 2-7 10 mM 33.5%                                                      Compound 2-8 10 mM 52.1%                                                      Compound 2-9 10 mM 52.6%                                                      Compound 3-1 1 mM 65.3%                                                       Compound 3-2 1 mM 52.6%                                                       Compound 3-3 10 mM 72.2%                                                      Compound 3-4 1 mM 60.3%                                                       Compound 3-5 10 mM 56.6%                                                      Compound 4-1 10 mM 49.3%                                                      Compound 4-2 0.1 mM 83.4%                                                     Compound 4-3 0.1 mM 75.3%                                                     Compound 4-4 0.1 mM 84.3%                                                     Compound 4-5 0.1 mM 72.6%                                                     Compound 4-6 1 mM 48.3%                                                     ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                                                      Hair growth                                         inhibition                                                                    3 weeks                                                                     Tested substance Concentration after shaving                                ______________________________________                                        Hydrolyzed almond (5% H.sub.2 SO.sub.4)                                                       1% (solid content)                                                                          82.5%                                             extract                                                                       Water extract of bumet 0.20% (solid content) 43%                              Ethanol extract of clove 0.20% (solid content) 66.3%                          Water extract of rose hips 0.20% (solid content) 54.7%                        50% Ethanol extract of hawthom 1% (solid content) 42.3%                       50% Ethanol extract of betula 1% (solid content) 31.3%                        Ethanol extract of gambir 0.20% (solid content) 35.6%                       ______________________________________                                    

From the results of Tables 8 and 9, it has been found that the compoundsof the formulas (1) to (4) had excellent hair growth inhibitory effects.

Formulation Example 1

According to the formulation as described below, a cream for alleviatingskin aging was prepared in a conventional manner.

    ______________________________________                                                              (wt. %)                                                 ______________________________________                                        Compound (1-5), (2-1), (3-5) or (4-3)                                                               0.2                                                       Stearic acid 2.0                                                              Cetanol 4.0                                                                   Squalane 8.0                                                                  Vaseline 5.0                                                                  Hydrogenated palm oil 4.0                                                     Polyoxyethylene sorbitan 1.4                                                  monostearate (20.E.O.)                                                        Lipophilic glycerin 2.4                                                       monostearate                                                                  Butyl paraben 0.1                                                             Glycerin 3.0                                                                  L-arginine 10.0 wt. % 0.2                                                     potassium hydroxide                                                           Perfume 0.1                                                                 Purified water        Balance                                                 Total                 100.0                                                   ______________________________________                                    

Formulation Example 2

According to the formulation as described below, a facial pack forpreventing or alleviating skin aging was prepared in a conventionalmanner.

    ______________________________________                                                              (wt. %)                                                 ______________________________________                                        Compound (1-5), (2-1), (3-5) or (4-3)                                                               3.0                                                       Polyvinyl alcohol 20.0                                                        Glycerin 5.0                                                                  Ethanol 16.0                                                                  Perfume 0.1                                                                   Coloring matter 0.1                                                         Purified water        Balance                                                 Total                 100.0                                                   ______________________________________                                    

Formulation Example 3

According to the formulation as described below, a hair growthinhibiting lotion was prepared. Described specifically, a solution ofcomponents belonging to A was prepared, while another solution ofcomponents belonging to B was prepared. To the solution A, the solutionB was added and they were mixed by uniform stirring, whereby a hairgrowth inhibiting lotion was prepared.

    ______________________________________                                                                 (wt. %)                                              ______________________________________                                        A:     Polyoxyethylene hydrogenated castor oil                                                             0.8                                                 Ethanol 30.0                                                                 B: Compound (1-5), (2-1), (3-5) or (4-3) 1.0                                   Sodium dodecyl sulfate 0.12                                                   Dodecyl methylamine oxide 0.18                                                Isopropyl alcohol 15.0                                                        Benzyl alcohol 12.0                                                           Glycerin 2.0                                                                      Purified water        Balance                                                 Total                 100.0                                            ______________________________________                                    

Formulation Example 4

According to the formulation as described below, a hair growthinhibiting aerosol was prepared. Described specifically, componentsbelonging to A were uniformly mixed and charged in a container. Thecontainer was then filled with B in a conventional manner, whereby thehair growth inhibiting aerosol was prepared.

    ______________________________________                                                               (wt. %)                                                ______________________________________                                        A:     Compound (1-5), (2-1), (3-5) or (4-3)                                                             1.0                                                   Cetanol 1.2                                                                   Propylene glycol 4.0                                                          Ethanol 8.0                                                                       Purified water      Balance                                            B:     Liquefied petroleum gas (propellant)                                                              4.0                                                   Total 100.0                                                                ______________________________________                                    

Japanese Patent Application No. 10-081418 filed on Mar. 27, 1998, isincorporated herein by reference in its entirety.

What is claimed is:
 1. A skin external preparation comprising a compoundrepresented by the following formula; ##STR16## wherein R²⁰ represents ahydrogen atom, a C₁₋₈ alkyl or alkenyl group or an aralkyl group,R²¹represents a hydrogen atom or a substituted or unsubstituted alkyl,alkenyl or aralkyl group, R²² represents a hydrogen atom or a C₁₋₆ alkylor alkenyl group, or with R²³, may form a heterocyclic ring togetherwith the adjacent nitrogen atom, R²³ represents a hydrogen atom or asubstituted or unsubstituted alkyl, alkenyl or aralkyl group, or withR²², may form said heterocyclic ring, R²⁴ represents a hydrogen atom ora C₁₋₈ alkyl or alkenyl group, and n stands for an integer of 0 to
 5. 2.A preparation according to claim 1 wherein said compound is of theformula: ##STR17##
 3. A preparation according to claim 1 wherein saidcompound is of the formula:
 4. A preparation according to claim 1wherein said compound is of the formula:
 5. A preparation according toclaim 1 wherein said compound is of the formula:
 6. A preparationaccording to claim 1 wherein said compound is of the formula:
 7. Apreparation according to claim 1 wherein said compound is of theformula:
 8. The skin external preparation according to claim 1, which isan agent for preventing or alleviating skin aging.
 9. The skin externalpreparation according to claim 1, which is a hair growth inhibitor.